Two types of adenosine deaminases exist in humans: ADA1 and ADA2. The primary role of ADA1, which acts as a monomer, is to eliminate intracellular toxic derivatives of adenosine and deoxyadenosine and to protect the cells from apoptosis (see, e.g., Franco et al., 2007, Crit. Rev. Immunol, 27:495-509 and Niisu et al., 1998, Blood, 92:3368-3375). The absence of ADA1 due to genetic mutations results in severe combined immunodeficiency (SCID) (see, e.g., Hershfield, 2005, Eur. J. Immunol., 35:25-30).
ADA2 (Adenosine Deaminase 2), also known as Cat Eye Syndrome Chromosome Region, Candidate 1, or CECR1, is an adenosine deaminase that catalyzes the deamination of adenosine and 2-prime-deoxyadenosine to inosine and deoxyinosine, respectively. In contrast to ADA1, ADA2 is a secreted homodimer and is highly expressed in plasma. ADA2 is highly expressed in dendritic cells, CD14+ monocytes, and lymphoid tissues, particularly in the thymus.
Recently, several groups have discovered that recessive loss-of-function mutations in CECR1, the gene encoding ADA2, can cause early-onset stroke and polyarteritis nodosa vasculopathy with highly varied clinical expression (Elkan et al., 2014, N. Engl. J. Med., 370(10):921-931 and Zhou et al., 2014, N. Engl. J. Med., 370(10):911-920). These loss-of-function mutations in humans reflect both impairment of the catalytic activity of ADA2 and the loss of its growth factor activities (see, Elkan et al., 2014). Current therapeutic options for ADA2-associated diseases and disorders are limited to management of symptoms using corticosteroid drugs or anti-TNF therapeutics. Thus, there exists a dire need to provide therapy for treating the root cause of the ADA2-associated diseases stemming from ADA2 deficiency by providing recombinant human ADA2 to patients and normalizing immunological signaling and cellular differentiation processes.